Inflammation is signaled by redness, swelling, heat and pain as a reaction of the body against injury or assault. A variety of chemicals have been implicated as chemical mediators of the inflammatory reaction, including histamine, serotonin, kinins, prostaglandins, leukotrienes, and, from nerve endings, substance P. Mediators of the acute inflammatory reaction seem to play roles in one or more of increasing vascular permeability, attracting leucocytes, producing pain, local edema and necrosis.
Each of the four signs of inflammation has been used by pharmacologists to establish methods for the detection and definition of anti-inflammatory substances. The inhibition of an induced edema, usually in the paw of a rat, has been a preferred method. Edemas can be induced in the rat or guinea pig models by means of UV radiation, irritants or heat. For example, thermal injury to the skin of animals produces an inflammatory response which is accompanied by erythema Erythema is part of the immediate response to injury which is followed by a delayed edematous response
There are steroid and non-steroid, anti-inflammatory drugs known to the art. U.S. Pat. No. 4,579,844, inventors Rovee et al., issued Apr. 1, 1986, discloses topically treating an inflammatory condition of the skin by use of the prostaglandin synthetase inhibitor concurrently with a corticosteroid. U.S. Pat. No. 4,404,198, inventor Kelley, issued Sept. 13, 1983, discloses the topical application of a composition including phenyl salicylate to treat inflammation. U.S. Pat. No. 3,980,778, inventors Ayer et al., issued Sept. 14, 1976, discloses a steroid for use in the topical, oral or parenteral treatment of skin and mucous membrane inflammations. Ibuprofen (a known anti-inflammatory agent) has been tested in connection with UV-B-induced inflammation, but was found to have limited usefulness in treating sunburn reaction and is only somewhat more effective than placebo for the relief of symptoms associated with UV-B-induced inflammation after high dose UV-B phototherapy for psoriasis. Stern et al., Arch. Derm., 121, pp. 508-512 (1985).
There are difficulties with presently used anti-inflammatory agents. Steroids, for example, are effective in reducing inflammation, but have some adverse side effects and tend to act fairly slowly.
Corticotropin Releasing Factor (hereinafter "CRF") is a 41 amino acid neuropeptide that is present in brain and the peripheral nerve endings, and stimulates ACTH release from pituitary cells. U.S. Pat. No. 4,489,163, inventors Rivier et al., issued Dec. 18, 1984, discloses rat CRF and its analogs. Human CRF has the same sequence as rat CRF. The amino acid sequence of both human and rat CRF is illustrated below: ##STR1##
There are a number of analogs of CRF known to the art. U.S. Pat. No. 4,415,558, inventors vale, Jr. et al., issued Nov. 15, 1983, discloses the synthesis of sheep CRF, analogs, and isolation of the oCRF from ovine hypothalamic extracts. The synthetic oCRF was found to lower blood pressure. The amino acid sequence of ovine (sheep) CRF is illustrated below: ##STR2##
A generally similar peptide, sauvagine, was described in Regulatory Peptides 2, 1-13 (1981). Sauvagine is a 40 amino acid peptide and has been reported to have biological activity in lowering blood pressure in mammals and stimulating the secretion of ACTH and .beta.-endorphin. The amino acid sequence of sauvagine is illustrated below: ##STR3##
U.S. Pat. No. 4,528,189, inventors Lederis et al., issued July 9, 1985, and U.S. Pat. No. 4,533,654, inventors Lederis et al., issued Aug. 6, 1985, disclose peptides similar to the rat and sheep CRF and analogs thereof, and found this white sucker and carp urotensin respectively to stimulate ACTH and to lower blood pressure. The amino acid sequence of carp urotensin is illustrated below: ##STR4##
The other CRF-related peptide, white sucker urotensin, has an amino acid sequence the same as the carp urotensin, except the amino acid at the 24 position is Isoleucine and the amino acid at the 27 position is Glutamic Acid.
Ling et al., BBRC, Vol. 122, pp. 1218-1224 (1984), disclose the structure of goat CRF, which is the same as that for sheep CRF. Esch et al., BBRC, Vol. 122, pp. 899-905 (1984), disclose the structure of bovine CRF which differs from sheep and goat CRF only by one amino acid residue (number 33 which is Asparagine rather than the number 33 Serine of goat and sheep CRF). Porcine CRF has been isolated and characterized by Patthy et al., Proc. Natl. Acad. Sci., Vol. 82, pp. 8762-8766 (1985). Porcine CRF shares a common amino acid sequence (residues 1-39) with rat/human CRF and differs from these only in position 40 and 41. Residue 40 can be either asparagine or isoleucine and residue 41 is phenylalanine-amide.
CRF has recently been found to inhibit the neurogenic plasma extravasation ("NPE") produced by antidromic stimulation of the rat saphenous nerve by intravenous injections of microgram per animal doses. Kiang and Wei, Eur. J. Pharmacol. 114, 111 (1985).
Many malignancies, such as brain tumors, spinal, oral, breast and nasal cavity cancers, are treated by radiation therapy whcch often results in painful inflammation of the covering skin or mucosa. Victims of exposure to smoke, hot air and tear gas experience inflammation of the trachea, and burn or scald patients experience painful skin inflammation. Patients undergoing U.V. treatment for psoriasis can experience sunburn as a side effect. There is a need for a direct, potent and fast-acting treatment to reduce or inhibit the acute inflammatory response acting on the skin and mucosal surfaces to thermal and/or radiation injury and from noxious agents, particularly in connection with cancer patients undergoing radiation therapy, victims of fires, and patients undergoing U.V. treatment, or the like.